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Importance of Early Identification and Diagnosis of HoFH


Early testing for HoFH may lead to significant improvement in patient prognosis.

Seth Baum, MD: Diagnosing homozygous FH [familial hypercholesterolemia] is a little difficult, as is diagnosing heterozygous FH. That’s the case because there’s a very large spectrum of presentation, a very large heterogeneity, of the disease. In homozygous FH, 2 guidelines help us make the diagnosis: the AHA [American Heart Association] guidelines and the European guidelines. They are very similar in many ways, with some important distinctions. In the AHA guidelines, we can make the diagnosis clinically based on phenotype or genetically. Genetic is easier. If you have 2 mutations in FH genes—LDL [low-density lipoprotein] receptor, APOB, or PCSK9—then you can make that diagnosis.

In the United States, we require an untreated LDL level, either greater than 560 mg/dL or greater than 400 mg/dL. This is with the stipulation that 1 other finding is present, either parents having heterozygous FH or the presence of xanthomas or aortic valve disease, with supravalvular aortic stenosis being the dominant disease occurring before the age of 20.

In the European guidelines, there are clinical and genetic ways to make the diagnosis of homozygous FH. The genetic are the same, obviously. In the clinical scenario, the opportunity exists to have a treated LDL level in addition to the untreated, which the Europeans set at greater than 500 mg/dL. In the treated LDL, it’s greater than 300 mg/dL. That’s important because oftentimes we see patients who are on a multitude of medications. We don’t know their maximum untreated LDL level. We can’t get it historically, so it’s nice to have some guidance. The difference in the clinical scenario with the Europeans is that those features of xanthoma or aortic valve disease have to occur before age 10. In the United States, we set that at age 20.

Erin Michos, MD, MHS: Heterozygous FH is probably a lot more common than we thought. We used to think that it was 1 of 500 individuals, but it’s more likely 1 of 250 or 1 of 300 because heterozygous FH is very underdiagnosed and underrecognized. That means homozygous FH is a little more common than we thought. We used to think it was extremely rare, such as 1 of 1 million, but it’s more likely 1 of 160,000 to 1 of 300,000 individuals. The reason it can be a little difficult to diagnose is that the range of LDL can overlap with heterozygous FH on the lower end of the spectrum.

As for the diagnosis of homozygous FH, it’s made if the LDL cholesterol is above 560 mg/dL, or above 400 mg/dLin the setting of having a parent who’s been diagnosed with FH, if the patient has a positive genetic test for FH, or if they have clinical signs such as aortic valve disease or xanthomas present before age 20.

Genetic testing for homozygous FH typically has homozygous in a null or complete defect in the LDL receptor. In these patients, this is incredibly high risk, with the onset of cardiovascular disease at very young ages, before the age of 20. There are individuals who have homozygous who are defective in the LDL receptor but not completely null, but their LDL receptors are defective. They have a slightly better prognosis with a little later cardiovascular disease onset, before the age of 30. Other individuals have compound heterozygous genes.

It’s important to have the genetic diagnosis because anybody with homozygous FH should be referred to a lipid specialist. Lipid specialists can initiate cascade screening, which is important for first-, second-, and third-degree relatives. Access to a lipid clinic can help silicate some of these important treatments, especially when you’re talking about the pediatric age and access to things like lipid apheresis. Other therapies, such as lomitapide, require enrollment in the REMS [Risk Evaluation and Mitigation Strategy] system. Onboarding other medications…may require paperwork and payer authorizations. Getting an individual in a lipid clinic can help initiate the onset of treatment as soon as the diagnosis is made.

When we’re talking about homozygous FH, the pediatric population is recommended to start lipid apheresis as early as age 7 for individuals with very high LDL. With lipid programs, in addition to having genetic counselors to do the genetic testing, it’s important for everybody with FH—homozygous or heterozygous—to meet with their registered dietitian to discuss a low-fat diet as a background for this medical therapy. Specialty pharmacies can help onboard some of these important lipid-lowering medications.

Transcript edited for clarity.

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