What to Know About Diagnosing, Treating Homozygous Familial Hypercholesterolemia

Eliot Brinton, MD, president of the Utah Lipid Center in Salt Lake City, talks about diagnosing and treating homozygous familial hypercholesterolemia (HoFH).

Hear Dr. Brinton talk about effective and emerging treatments for HoFH.

Question:

Could you give a brief summary of homozygous familial hypercholesterolemia, covering its etiology, pathophysiology, and clinical manifestations?

Eliot Brinton, MD:

Homozygous FH is really a continuum of heterozygous FH. It’s kind of all 1 spectrum, and we all see patients with the milder version of FH, which is heterozygous FH.

What is FH? FH is a monogenic genetic disorder. It’s co-dominant. Heterozygotes have moderate disease. Homozygotes have a much more severe disease. How does this happen? What’s the pathophysiology? This boils down to LDL receptor function. The liver is the organ tasked with the removal of LDL, and this is primarily through the LDL receptor, and any large gene defect in the gene for the LDL receptor itself or for the major ligand of the LDL receptor, which is apolipoprotein B, or in proteins that help process the LDL receptor, and there are several of them.

These are all candidates for causality of FH, heterozygous and homozygous. If you have 1 major gene defect that will knock down your activity of the receptor and the ability to clear LDL from the circulation by roughly 50% or so. If you have 2, then it can knock it down at that much more. But realize that this depends, in part, on the severity of the mutation.

Strictly speaking, heterozygous FH can be anything from fairly mild to more severe, and homozygous FH also can be relatively mild to more severe depending on the degree of impact of the mutation on the protein function. A key question here is, what are the clinical manifestations of FH? Again, focusing on homozygous FH, typically these patients present in childhood or adolescence or young adulthood primarily with very severely elevated LDL cholesterol levels. We’re talking about LDLs generally between the 300 and 900 mg/dL range. In the more severe range, they can present with xanthomas that are not the typical tendon xanthoma that we think of with heterozygous FH, but more often soft xanthoma on the skin, such as in the creases between the fingers or maybe on the feet or back of the knee.

There are various places where these skin xanthomas can present and they’re soft; they’re yellow. Often, the diagnosis is made by a dermatologist who’s called upon to biopsy and the xanthomas are full of cholesterol, cholesterol ester, and that’s pathognomonic for FH and generally homozygous FH if these present younger in age and in the skin.

Another key element here is the atherosclerosis. In fact, that is the major problem. The xanthomas are not really an issue. [They’re a] very minor cosmetic issue. [With] heterozygous FH, a patient will get a heart attack and strokes in middle age, but in homozygous FH, it’s only the milder cases that can last that long. In most cases, people can present as adolescents or as children or even very young children with cardiovascular disease, and they can have angina, they can have a heart attack, they can have a stroke. It’s very devastating because you can imagine if it’s hard enough to face this as an adult, as a young adult or adolescent or child or maybe very young child, it’s just that much more difficult.

Question:

What are the main challenges in treating patients with homozygous familial hypercholesterolemia, given its rarity and serious cardiovascular consequences?

Eliot Brinton, MD:

The key challenge to managing these patients has to do with, first of all, understanding the need for a lipoprotein profile and the need to take that lipoprotein profile seriously. If an adolescent has an LDL that’s just a little bit over 160, we think maybe that’s heterozygous FH; in adults, maybe a little bit over 190.

But patients with homozygous FH will have much higher LDL levels. We look to those LDL levels, and if they’re way above range, then we need to think this is either a very severe case of heterozygous or maybe a mild-to-moderate-to-severe case of homozygous FH. We look at the xanthomas; the presentation might be angina, but then paired with these atypical xanthomas that are actually pathognomonic for homozygous FH, that’s how we then are thinking this may be homozygous FH.

It’s very rare. We’re talking about between 1 in 8 per million individuals in a population. In the back of the mind, we always have to be thinking, are we going to see a very severe cluster elevation and might this be homozygous FH? The first challenge is making the diagnosis and realizing that this is something that requires very aggressive treatment, and that would be then to prevent very early disease.

Question:

How do you make treatment decisions for patients with homozygous familial hypercholesterolemia? What are the pharmacological and/or non-pharmacological interventions that you typically utilize?

Eliot Brinton, MD:

The second challenge then is figuring out exactly how to treat. We always start with our standard LDL lowering treatments, and that is first and foremost the standards. They lower LDL by generally between 30% and maybe 55% or 60%. They lower cardiovascular events by almost that same degree, but that is in a polygenic hypercholesterolemia or in the heterozygous patient. That’s where these standards work very well.

In a homozygous FH patients, ironically, in the setting of a higher baseline LDL, the standard medications work less well. As you can imagine, this makes it really, really hard to treat these patients. We get whatever we can get with a statin. We try to go to the higher dose, the more effective statins if possible, but they may not be tolerated by the patient. Then we will always go to ezetimibe. Ezetimibe is generic, very cheap lipostatin.

It’s not quite as effective, but it has the effectiveness of three doublings of a statin dose quite effective in the non-HRFH. Sadly in the HoFH patient, it may give us very little, if any, LDL lowering. A quick rule of thumb is that you get half or maybe far less than half of the usual LDL lowering if a patient has FH, especially homozygous FH.

Sometimes we then go into bempedoic acid. This is a new agent. It’s only available as a branded product, but it’s effective as an adjunct to either ezetimibe or to a statin.

The fourth class, which we use always in these patients, are the PCSK9 inhibitors. These are either the monoclonal antibodies or the SNNA: evolocumab, alirocumab, and glycerin, and these are much more effective in the non-HoFH patient. We expect 50% to 60%-plus LDL lowering, so even more effective than the statins.

But again, as you get into the higher ranges of baseline LDL, that indicates less baseline LDL receptor activity. All 4 of these classes of drugs work by upregulating existing LDL receptor. The PCSK9 inhibitors, which are so, so helpful outside of homozygous FH, in the case of homozygous FH, we may get a 30% LDL lowering or even much less. They can be used in homozygous FH that are indicated for that, but only in the milder cases are they truly very effective. But we get to kind of a dividing line between the treatment of the milder FH patients and the more severe FH patients, the homozygotes, and that is the standard LDL receptor-based versus the non-LDL receptor-based treatments.