Homozygous familial hypercholesterolemia: a condition that is underdiagnosed
Joshua Knowles, MD, an Associate Professor of Cardiovascular Medicine at Stanford University, talks to Rare Disease 360 about diagnosing and managing homozygous familial hypercholesterolemia (HoFH).
Question:
HoFH is a rare condition that is underdiagnosed. How can this underdiagnosis be remedied? What is the role of genetic testing?
Joshua Knowles, MD:
Homozygous familial hypercholesterolemia is a devastating condition. It’s caused by genetic mutations that impair the body’s ability to recycle LDL cholesterol. LDL cholesterol is like a waste product that needs to be recycled. In patients with homozygous FH, they’ve inherited mutations that completely abolish the body’s ability to recycle this cholesterol. That leads to toxic levels of blood cholesterol over time that damages blood vessels and leads to a huge increased risk for heart disease. Many patients with homozygous FH have heart disease by the time they’re teenagers. Sometimes they need bypass surgery, some patients even get liver transplant to correct the mutations that act in the liver. It’s really important to recognize homozygous FH because it is treatable if it is intervened on early. Treatments involve multiple medications, often 3, 4, 5 medications, and sometimes even a dialysis-like procedure called apheresis that removes blood cholesterol. With those proper treatments, the disease onset of coronary disease can be delayed greatly, and we’re in a golden age of treatment for homozygous FH patients. They have more hope than ever.
With that in mind, it’s really important to keep in the front of our mind that this can happen in our practices, especially in children. Things that should raise the specter of homozygous FH should be a family history of early-onset heart disease, high cholesterol. The patients with homozygous FH can develop xanthomas, cholesterol deposits in tendons of their hands, their Achilles, and other places. I think the most important thing is that the eye cannot see what the mind does not know. You really need to understand familial hypercholesterolemia to understand who’s at risk. We have a saying at the Family Heart Foundation, which is we never find an individual with FH, we only find families with FH. If there are parents with high cholesterol or parents with early-onset heart disease, then we need to be especially thinking about children and siblings, grandparents who also might be at risk.
For an individual to have homozygous FH, it means both parents have to be affected by heterozygous FH. Homozygous FH affects the kids because they have inherited one bad copy of a gene from dad and one bad copy of a gene from mom, and that together has led them to get homozygous FH. These children often have LDL cholesterol levels over 500 mg/dL. Just recall, for the American population, the average LDL cholesterol is about 130 mg/dL, and a healthy LDL cholesterol as well under 100 mg/dL. It’s really important to screen, to think about it, to offer testing. The American Academy of Pediatrics has recommended that all children be screened for cholesterol issues during childhood because if we find this, we can intervene in a timely way. Not just with medications but also with diet, with lifestyle, with exercise. But less than 5% of children have been screened for cholesterol, which is something that we should strongly advocate for change.
Question:
How do you counsel patients and families about HoFH at diagnosis?
Joshua Knowles, MD:
I’m an adult cardiologist, so a lot of times by the time patients get to me that have homozygous FH, they were already diagnosed in childhood. The pediatricians and the pediatric cardiologists and lipid specialists and endocrinologists that have been taking care of them have often done a lot of counseling. But one of the things that we have to do is we have to emphasize that this is not a death sentence. There are effective treatments that are available. It often requires multiple medications and other things. That there are centers of excellence around the country that give a lot of hope to homozygous FH patients. We also have to emphasize to them the familial nature of this. A lot of times when we see a homozygous FH child, the parents are doing everything they can to take care of the child, but they’re neglecting themselves.
They are obligate carriers of this condition and so they also need to take care of their own cholesterol levels so that they can be there for the kids. There are centers of excellence around, there are also communities of FH patients and homozygous FH patients and parents of homozygous FH patients. There are great resources at the Family Heart Foundation to connect those patients with each other and the communities and give them support and knowledge that they need. This is a lifelong condition that requires aggressive lifelong therapy, but with that comes a longer lifespan, less heart attacks, and less problems.
Question:
What are treatment and management options available to patients who have HoFH?
Joshua Knowles, MD:
The treatment options are more than they’ve ever been before; 20 or 30 years ago, the treatment options were somewhat limited. We had statin medications, we had bile acid binding resins, and we had apheresis, which is a dialysis-like procedure to reduce cholesterol levels. But unfortunately, in many homozygous FH patients, the traditional medications do not work that well. Many of the traditional medications act by increasing the body’s production of the receptor for LDL cholesterol, the LDL receptor, but in homozygous FH patients, often those receptors don’t work very well. We need specific medications in many cases that act through non-LDL receptor mechanisms. Now in the last 10 or 12 years, multiple medications have come out. Lomitapide and evinacumab are 2 examples of specific homozygous FH medications that work through LDL receptor-independent mechanisms that have been usually very effective. They also have apheresis, which continues to be available.
For homozygous FH patients, it’s often critical to their management. Traditional medications, statins, PCSK9 inhibitors, ezetimibe can play a role, and in some patients, they play more of a role than others. They’re more effective than others depending on the specific mutation that you have. Genetic testing for homozygous FH does play a role. It confirms the diagnosis and it has some implications for what medications be useful. It has implications for screening family members. In true homozygous FH patients, the genetic testing is usually positive.
