What you should know about the diagnosis, treatment, and management of homozygous familial hypercholesterolemia

Carissa Baker-Smith, MD, MPH, associate professor of pediatrics and cardiology at Nemours Children’s Hospital in Wilmington, Delaware, discusses the importance of screening for homozygous familial hypercholesterolemia and the different treatment options for the condition.

Hear Dr. Baker-Smith talk more about individualized care in part 2 of this video series.

Question:

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic condition that can lead to premature cardiovascular events, particularly in young children. What should physicians and the public know about HoFH, and how can the community improve awareness to promote earlier diagnosis and treatment?

Carissa M. Baker-Smith, MD, MPH:

One of the things, just as you mentioned, is just recognizing that the disease exists, recognizing that there is an entity called homozygous familial hypercholesterolemia. Likewise, there’s heterozygous familial hypercholesterolemia. Knowing that there are inherited causes of high cholesterol that increase one’s risk for premature heart-related events, and that includes heart attack, myocardial infarction.

The other key point is recognizing that you must be screened for them. Recognition that often, we don’t know that we have the condition unless the laboratory test is drawn, unless the cholesterol is checked. It’s not enough for, and I’ve heard this, it’s not enough to say, “Oh, I feel fine.” You will feel fine until you don’t feel fine.

Unfortunately, things like high cholesterol, they’re usually asymptomatic, like I said, until they’re not. But that doesn’t mean that the effects aren’t happening under the surface. It’s like the shakiness underneath the ground before the earthquake, right? It’s happening, even if you don’t realize that it’s happening.

Screening is very important. We recommend at the very least, lipid screening, cholesterol screening between 9 and 11 years of age and 17 to 21 years of age, both of those time periods. But if you have a family history, if you know that you have a family history of premature heart attack, so that’s an event like coronary artery stents or an actual heart attack in a first-degree relative like a mother or father before 55 years of age in men or 65 years of age in women who are premenopausal, that’s premature. Knowing that, that means that that particular person’s child needs to be screened for high cholesterol as early as 3, if possible.

The other thing to note, the third thing to note, is that high cholesterol, like homozygous FH, usually those LDL levels, the bad cholesterol, they’re at least 300 mg/dL. It’s at a very young age. We’re talking about as early as 3. You won’t necessarily know that a child has that level of high cholesterol unless the testing is done.

Now, there is something to note that’s a little different about homozygous FH than heterozygous FH. Homozygous FH means that you basically have 2 parents that were affected with heterozygous FH. Two parents that have genetically inherited high cholesterol, the child has homozygous FH. They can have congenital heart defects too. Their exam may not be normal. I do want to put that out there.

But in some cases, there are individuals who have this very high cholesterol level and no one knows unless they’re tested. Don’t go by a feeling, don’t go by, and I’ve heard this, don’t go by this assumption that just because you feel fine, everything must be fine. Really, the way that we’re going to prevent disease and prevent that early event, early heart attack, is to get diagnosed and is to get treated. I do want to urge parents.

Last thing I’ll say, and I really want people to take this home and providers to know this too, not every high cholesterol that you see is related to diet. Not everything that you see is related to lifestyle. There truly are inherited forms of high cholesterol that regardless of how good your diet, you could eat carrots and broccoli every day and that’s all you eat, and your cholesterol could still be high. It’s the recognition that those individuals are there because 90% of people who have FH, familial high cholesterol, they don’t know they have it. Many unfortunately won’t know until it’s too late.

One in 250 people have heterozygous. One in about 300,000 to 1 in a million have the homozygous form. It seems rare, but it’s still something that we want people to be aware of so that you can get screened, tested, diagnosed, treated, so that you don’t have to have that early event. Trust me, I’ve heard enough stories, I’ve interacted with enough families, loved ones, to know that it can be devastating when that event happens and you’re unprepared.

Question:

What are the treatment options available to patients who have HoFH and how do you counsel patients and families at diagnosis?

Carissa M. Baker-Smith, MD, MPH:

For homozygous FH, it’s a little different than heterozygous, and you’ll hear me go back and forth. I just want to be clear, homozygous is typically that you have 2 bad genes, and then heterozygous means you have 1 good gene and 1 bad gene. I’m just going to pause here and just say, when we talk about genes, we’re talking about your genetic makeup, but we’re talking about how cholesterol, which we all normally make, is removed from the body. We all have these receptors. They’re little things on the liver cells. They take that cholesterol and they’re supposed to process it, and we get rid of it.

But some of us, those of us who have FH, those receptors don’t work. If you have heterozygous, you have some receptors that work, some that don’t work, right? Your LDL, bad cholesterols, in the 200 range. If you have homozygous, really less than 15% of those receptors work. As a result, your LDL levels are at least 300, sometimes 400, sometimes 500, sometimes more. Then you have all this extra cholesterol in the blood, and too much of a good thing is a bad thing. We do need cholesterol, but too much, it gets into the walls, it irritates the walls of the arteries. It sets up for atherosclerosis.

If you have too much cholesterol in the blood, how do you get rid of it? Well, you have homozygous FH. Lipid apheresis is one treatment, that is kind of like a dialysis machine. You get connected to the machine, we wash the blood, we wash the cholesterol out, but before that, we will try medication, right? You’ll try to upregulate the number of receptors that are available, even if some don’t work. Statins and some people will try PCSK9 inhibitors; we’ll try to decrease the amount of cholesterol that you absorb in your diet through something like ezetimibe, so Zetia.

We will try medications, but often in homozygous FH because those receptors, they just don’t work. The statins and the Zetia, they’re just PCSK9 inhibitors; they’re just not going to be effective enough. Then we have this option of lipid apheresis, and like I said, it’s kind of like dialysis. You connect to a machine and that machine will take the blood, wash the cholesterol out, and returns the blood to the patient, takes about 4 hours.

The other agents that are available for kids who have homozygous FH, we have a new medication on the market. For full disclosure, I was one of the site primary investigators for this trial for kids that we have, evinacumab, and it’s a medication, it does not work through the LDL receptor. It works differently, helps to lower the cholesterol level, works pretty good, lowers the cholesterol by about 50%.

There’s some newer agents that are coming in the market, Inclisiran is on the market, I think for adults, it acts at the micro mRNA levels so it’s pre protein. It helps to decrease the PCSK9, so you don’t get this recycling of the receptor. You have more around. Those are some of the medications that are out there and therapies that are out there for homozygous FH.

It’s interesting, before evinacumab, and centers don’t have lipid apheresis, and this isn’t what we tend to do nowadays, but liver transplant was a treatment for homozygous FH. We don’t do that anymore, but at least not routinely, that I’ve seen. But like I said, lipid apheresis, which is again physically washing the blood about four hours and some of these medications that I’ve mentioned.

Evinacumab has been a game changer in some ways so that kids, not that they don’t have to get the lipid apheresis, but they don’t get it as often. Instead of having to get connected to that machine once a week, maybe it’s every 4 weeks, which gives them time back in terms of being able to be involved in school activities and the like.