Presented by: Joshua Knowles, MD, PhD
Assistant Professor, Cardiovascular Medicine
June 11, 2015
Familial hypercholesterolemia (FH) is an inherited disorder that causes extremely high levels of LDL (low density lipoprotein or “bad” cholesterol), and no amount of diet or exercise can bring the numbers down. If not treated, these LDL levels can build up in the arteries and lead to heart attacks at an early age.
It affects about one in every 250 people, but few realize they have the condition and it is often overlooked by physicians who do not normally test for cholesterol in children. It’s estimated that more than one million Americans—both adults and children—have the disease.
Despite the fact that FH is under-reported and under-treated in the United States, the disease is more common than cystic fibrosis, muscular sclerosis, or Marfan syndrome. Many people don’t even know they have it until they have a heart attack.
FH is an underlying cause for more than 12,000 heart attacks each year among people under age 60 in the U.S., Knowles said. It often affects entire families, and children have a 50 percent chance of inheriting it from their parents.
“Most people start to suffer the consequences of cholesterol buildup in their 60s and 70s, but people with FH start to show the effects of high cholesterol at a much younger age, often in their 30s and 40s,” said Joshua Knowles, MD, PhD, an assistant professor of cardiovascular medicine, who spoke at a presentation sponsored by the Stanford Health Library. “If not treated, people with FH have a 20-fold increased chance of a heart attack.”
The disease is treatable, and as much as 80 percent of FH-related heart attacks are preventable, he said. “FH is very treatable, but it is estimated that less than 10 percent of the U.S. population has been diagnosed,” he said. “With treatment, people with FH can live a long, healthy life.”
Cholesterol is essential for the body to function properly. But high levels of cholesterol can cause fatty deposits (plaques) inside the blood vessels, leading to atherosclerosis and conditions ranging from peripheral artery disease to stroke. An optimal level of LDL (measured in milligrams per deciliter of blood) is under 100; however, people with FH have an average LDL of 220 and can reach levels of more than 500.
“Since FH causes high LDL from birth, cholesterol accumulations just get higher over time, creating a cumulative effect” he said.
A Family Concern
“We always say we never just find an individual with FH—we only find families with FH,” said Dr. Knowles, who emphasized the importance of cascade screening to help identify close family members who have a genetic mutation. Cascade screening is a mechanism for identifying people at risk for a genetic condition by systematic tracing the family. If one person has the disease, all of the first-degree relatives (mother, father, siblings, and children) have a 50-50 chance of having it and should be tested as well.
“A diagnosis is based on a careful family history and a physical exam,” he said. “People with FH are more likely to have a family history of high cholesterol and heart disease at a younger age than normal.”
Although high LDL levels is the primary warning sign, there can also be physical symptoms, such as discoloration of the iris in the eye and cholesterol deposits at the tendons (called xanthomatas) or around the eyes.
Most cases are caused by a mutation in one of three genes associated with lipid removal in the liver: LDLR, APOB, and PCSK9. These mutations prevent the liver’s cellular receptors from pulling LDL particles from the blood, prevent the LDL from binding to the receptor, or degrade the receptor so it no longer functions.
Efforts are underway to promote cascade screening and educate people about the disease. In the Netherlands, national efforts led to the initial identification of approximately 5,000 people with FH through lipid and DNA testing, which led to screening of more than 60,000 family members. By applying cascade screening, the researchers identified more than 27,000 people with the disease and were able to prescribe preventive medication.
“The study showed that finding and treating FH in this manner is both cost-effective and benefits health,” Dr. Knowles said. “It also hints that when you give people genetic information, it tends to improve outcomes.”
Treatment for FH includes sticking to a diet low in saturated fat and high in fiber, and healthy lifestyle choices like regular exercise and no smoking. But diet and exercise alone are not sufficient since these changes tend to bring about only a 15 percent reduction in cholesterol levels—FH patients need to reduce their numbers by more than 50 percent.
Cholesterol-lowering statin drugs are prescribed, with the goal of bringing LDL levels below 100. However only about 40 percent are able to get below 130 and only 20 percent are able to reach 100. Many patients require prescriptions for two or more different cholesterol lowering medications.
Dr. Knowles is involved with the FH Foundation, a nonprofit organization established to educate people about the disease and advocate for awareness and detection through cascade screening and a national patient registry. He hopes to address the gap in knowledge among both patients and physicians, and help people understand their options.
It’s a winnable battle,” he said. “We’ve learned that patient participation in FH research can drive the outcome.”
About the Speaker
Joshua Knowles, MD, PhD, is an assistant professor of cardiovascular medicine. He received his MD and his PhD in genetics and molecular biology from the University of North Carolina at Chapel Hill. He did his internship, residency, and fellowship training at Stanford. An expert in FH, Dr. Knowles is the chief medical advisor of the FH Foundation, a national nonprofit that raises awareness of familial hypercholesterolemia.
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