HoFH Diagnostic Criteria, Prevalence, and Genetic Factors
Seth J. Baum, MD, Chief Medical Officer of Flourish Research and the Vice-Chair of the Board of the Family Heart Foundation, talks about the prevalence of homozygous familial hypercholesterolemia (HoFH) and when screening for the disease should occur.
Question:
What are the key clinical features and diagnostic criteria for homozygous familial hypercholesterolemia (HoFH)?
Seth J. Baum, MD:
HoFH or homozygous familial hypercholesterolemia is an ultra-rare inherited disorder of LDL metabolism. Its prevalence is somewhere around 1 in 300,000. There are over 1,000 individuals in the United States with homozygous FH or HoFH. It’s imperative that we identify these individuals at a young age and we treat them appropriately. We have to have certain clinical guidelines and genetic guidelines to be able to make that diagnosis. There are 2 ways that we can make the diagnosis. One is clinical or phenotypic, and the other is genetic.
There are many different systems in place to be able to do this, but the American Heart Association has one that’s been around since 2015 that’s very useful. If individuals have an LDL on no therapy of 560 or above, they automatically are categorized as having HoFH. If they have an LDL 400 or above, again on no therapeutics, but have other things in association with that, such as knowing that both parents have elevated cholesterol or EGFH, that works for the diagnosis, or if they have supervalvular or stenosis or tendon xanthomas at a young age. These are different ways to make a clinical diagnosis. Also, many people use greater than 300 on therapies because we don’t always know what the patient’s baseline LDL is. We see them when they’re already on drug, and we’re certainly not going to take them off to find out. If it’s greater than 300, that can qualify.
Genetically, we’d have to identify a mutation from mother and a mutation from father. Two different mutations affecting the LDL receptor, either LDL receptor mutations or ApoB or PCSK9. Those are the most common ones. LDL receptor being the most common one, 90-plus percent of the patients. Then there are different types of mutations that people can have, meaning… the most one would be what we call true homozygous, which is the exact same mutation of the LDL receptor inherited from mother and from father. Each parent has the exact same mutation.
The next most common one is called compound heterozygous, and it’s a very misleading name because although we call it compound heterozygous, it’s actually homozygous, so very confusing. But that would be typically the same gene, but a different mutation. Typically, that’s the LDL receptor. Same gene, different mutation, so 2 LDL receptor mutations, but different: one from mother, one from father. The third is called double heterozygous, also confusing. Double heterozygous, which is another form of homozygosity, would be a different gene with the mutation each from mother and father. For example, LDL receptor and ApoB mutations would be the most common form of that. Again, over 90% of patients have LDL receptor mutations. Most of those are the “true homozygous,” but there are plenty of the others around.
The problem with making a genetic diagnosis is we have not identified all the mutations that are responsible for homozygous FH or FH in general. As a consequence, if you rely solely on genetics, you can miss individuals who require very important treatments. We always say that the clinical or the phenotypic diagnosis trumps the genotypic one. If you have a genotype where you’ve found one mutation, but the patient clinically has homozygous familial hypercholesterolemia, then that patient has HoFH, even though the genetics don’t confirm it. That’s very, very important to know.
Another aspect of this is how do you identify these patients? I just gave you the clinical criteria, but when do we look at LDLs? At what age do we look? There are 2 different types of screening. There’s targeted screening, there’s universal screening. In the case of LDL, there are a few different times in life where we should do targeted screening. First is birth to 2 years old, and that would be for a child of parents who both have heterozygous FH or very elevated cholesterol. Those kids should be screened between birth and 2 years old. Unfortunately, that’s not happening that frequently.
Then there are a couple of times in the 8-year and up to 16-year range where there are other opportunities to do targeted screening, and that would be done in individuals who have other high-risk features, hypertension, diabetes, such things. If you have a very high-risk patient, you’d want to do a targeted screening at a young age. For universal screening, meaning everybody should have universal screening, everybody has screening at this point, it’s between the age of 9 and 11. Every child between 9 and 11 should have a lipid profile. Unfortunately, that doesn’t happen often enough.
Then later on before the age of 20, there’s the opportunity to do another universal screen to again, make sure we’re not missing people who have FH. The risk, and we’ll get into that, is so high that you want to identify these individuals early on in life.
Question:
How prevalent is HoFH and what are the genetic factors that contribute to its development?
Seth J. Baum, MD:
In terms of prevalence, that number has shifted. We used to think HoFH occurred 1 in 1 million individuals. Now we understand that it’s much closer to 1 in 300,000, so much more prevalent than we previously thought. Heterozygous FH, which we used to think occurred at about 1 in 500, now we say between 1 and 200 and 1 in 225, somewhere in that range. Again, the genes that are most commonly involved in causing familial hypercholesterolemia, well, the first one is the LDL receptor, and then the other two are ApoB and PCSK9. Those are the genes that experience the mutations that are pathogenic, that lead to faulty LDL receptor functionality, basically. That’s the common denominator.
