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Biotechnol Healthc. 2010 Spring; 7(1): 8–9.
PMCID: PMC2873730

Familial Hypercholesterolemia Captures Gene Test Controversies

Bob Carlson, MHA, Senior Contributing Editor

You can’t watch This Week with George Stephanopoulos, or riffle through The Economist without being inundated with ads for statins.

Hypercholesterolemia may be the most medicated disease, and anyone on statins likely got there because of a fondness for high-dietary cholesterol, saturated fat, and a sedentary lifestyle.

Familial hypercholesterolemia (FH), on the other hand, is caused by inherited mutations in the LDL receptor gene. Someone with heterozygous FH (one parent contributes a genetic mutation) typically has a total cholesterol count of 300 to 400 milligrams per deciliter and a level of low-density lipoprotein (LDL), the “bad” cholesterol, in excess of 200 mg/dL. Homozygous FH (both parents contribute genetic mutations) is characterized by a total cholesterol level that can reach 1,000 mg/dL. Either type is deadlier than acquired hypercholesterolemia.

FH is not one of those rare genetic diseases that most of us do not have to worry about. The prevalence of heterozygous FH in the U.S. is 1 in 500; about 600,000 young and middle-aged Americans have this disease. You will not find many older adults in this cohort because people with FH often do not live that long. Homozygotic FH is found in 1 in 1 million Americans and kills even sooner.

“Approximately half of untreated [heterozygote] males will have had a heart attack by 45. For women, that will be closer to 55 or 60,” says Paul N. Hopkins, MD, MSPH, professor of internal medicine and codirector of cardiovascular genetics at the University of Utah School of Medicine.

For untreated FH homozygotes, the prognosis is down-right tragic. Heart attacks have been documented in 2-year-old infants and more frequently at ages 8, 10, and 12 due to extremely aggressive coronary atherosclerosis. Untreated, most FH homozygotes will have heart attacks in their late teens, and few will survive past their 20s.

“A few people who look like they have FH actually have a bad apolipoprotein B [APOB] gene, which does not bind well to the LDL receptor [LDLR]” Hopkins continues. “The prevalence of Familial Defective Apolipoprotein B-100 [FDB] is 1 in 1,000, so those are a minority of cases of FH hypercholesterolemia. Clinically, you can’t tell the difference between those who have FH due to the LDLR being bad versus those who have a defect in the APOB gene.”

Genetic testing can identify genetic mutations associated with FH, but physicians order such testing infrequently. “We’ve only done a few hundred of the tests available,” says Michael W. Henry, vice president of business development at Athena Diagnostics, a CLIA-accredited lab and a subsidiary of Thermo Fisher Scientific, in Worcester, Mass. Henry is referring to Athena Diagnostics’ LDLR (Hypercholesterolemia) DNA Sequencing Test and APOB (Hypercholesterolemia) Mutation Analysis, which were launched in 2005 under license with Correlagen Diagnostics. The LDLR test identifies autosomal dominant loss-of-function mutations in the LDLR gene, which codes for the LDLR. The APOB analysis identifies autosomal dominant loss-of-function mutations in the APOB gene, which codes for apolipoprotein B-100, the principal protein component of LDL.

Routine lipid screening, starting in infancy, would diagnose most Americans with FH, and treatment would dramatically increase their quality of life and lifespan. For FH heterozygotes, statins are usually effective if therapeutic lifestyle interventions are unsuccessful. For FH homozygotes, the only effective therapy is weekly or bimonthly LDL apheresis, which is analogous to renal dialysis.


Unfortunately, screening lipid panels, diagnosis of FH, and treatment of FH are not routine — leaving the 600,000 or so Americans with FH at risk of atherosclerosis, heart attack, and premature death., now hosted by the National Institutes of Health’s National Center for Biotechnology Information, lists 23 laboratories worldwide that do genetic testing for FH, with six in this country. If orders for FH genetic assays are lacking, it’s not because the sales forces haven’t been busy.

“All of them,” is Hopkins’ reply when asked if he’s been contacted by sellers of genetic tests for FH. “I have probably seen and documented more FH at our center than anybody in the country, so they’re anxious to get our business. But most of us that have experience in FH, especially in the United States, have gotten along very well without those genetic tests and with very high certainty that the people we diagnose indeed have the disease.”

Hopkins has nothing against the tests. He just does not think they’re needed to diagnose most patients with FH — they don’t change how hypercholesterolemia is treated, he says, and they add cost. For example, Athena’s LDLR test costs $1,235, the APOB test is $620, and the hypercholesterolemia evaluation, which combines the LDLR and APOB tests, is priced at $1,485. These prices may be reasonable for genetic tests but are unnecessary cost for FH, says Hopkins.

Athena has a national contract with the Blue Cross Blue Shield Association to cover all its tests, says Henry.

Hopkins begins to suspect FH if the LDL level is above 190 or 200 mg/dL. Subcutaneous cholesterol deposits along the Achilles or finger extensor tendons support an FH diagnosis. As the disease is heritable, a family pedigree and screening lipid panels of family members can identify those with the disease and so they can be treated.

Hopkins’ diagnostic approach seems fairly straightforward, but most primary care physicians are not educated about FH, he says. “They have the mistaken impression that familial hypercholesterolemia is super rare.” As for the physicians who do order these tests, Hopkins chalks it up to inexperience most of the time. “Those usually are the ones who don’t realize how well you can do by simply looking at a pedigree of cholesterol values. If you have one case of very early coronary disease with an untreated LDL of, say, 280, you start looking for cholesterol in the family, and if you find a brother with an LDL of 260, then you have a definitive diagnosis of FH. With all the hoopla about genetic testing and personalized medicine, FH may be the only disease for which family screening is really warranted.” Hopkins allows that he might order a genetic test for a family with borderline LDL levels or for an adoptee without access to a family pedigree who wants to know his or her FH status for family planning purposes.

“It’s still early days for these tests,” Henry adds. “There are not going to be much data out there on outcomes using these tests, and they haven’t been around long enough for professional societies to develop guidelines.”


The closest thing to practice guidelines for FH is a paragraph in the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III),and the words “genetic testing” are not even mentioned. But that may change. Published in 2002, the report is due to be updated soon, according to Robert D. Shamburek, MD, a researcher in National Institutes of Health’s (NIH) Translational Medicine Branch of the National Heart, Lung and Blood Institute and head of the lipid clinic at the NIH Clinical Center in Bethesda, Md., where he has been seeing dyslipidemic patients, including those with FH, for 15 years.

Unless the NCEP expert panel, the National Lipid Association, or the American Board of Clinical Lipidology come up with new guidelines, FH is likely to be detected, diagnosed, and treated as the NCEP report recommends, which is what Hopkins, Shamburek, and other lipid experts do now. Even if guidelines change to include genetic testing, a variety of systemic disincentives may stand in the way. For example, in 2008, the American Association of Pediatrics recommended that all children between the ages of 2 and 10 be screened, especially if they have a family history of coronary artery disease.

“That alone would pick up probably the majority of patients with FH,” says Shamburek. “But when you’re dealing with patients who are under 18 years of age, you’re probably never going to see coronary artery disease. It’s not as big on our radar as other pediatric diseases. We’re very, very poor in the United States with primary prevention.”


National payers get lower unit prices on genetic tests, and many European countries routinely screen their citizens for FH using the so-called Simon Broome criteria, which include “DNA-based evidence of an LDLR mutation or FDB.” Both Hopkins and Shamburek talk about the FH screening programs in the Netherlands, Italy, Norway, France, and Spain with admiration.

“They have wonderful screening programs that are subsidized by the government, the Netherlands being the best example,” Hopkins says. [Patients] get referred to lipid clinics and [physicians] monitor their progress. They recognize that you actually spend less money in a lifetime if you start statins in the 20s or 30s, so they provide statins for life if you have an LDLR mutation. Could they have done it without the mutation testing? I don’t know.”

As Shamburek points out, “You always ask yourself, if I order a test, is it going to change what I’m going to do? I think in this case, it wouldn’t. If the test came back negative, I would still treat the patient. So you could ask, is DNA testing a luxury or a necessity?”

As the cost of genetic testing continues to decline, paying for LDLR and APOB mutation testing will presumably become less of an issue. Meanwhile, conventional lipid panels are already cheap, and with more than 90 percent specificity and sensitivity, “pretty dang good” in Hopkins’ opinion.

“You might pick up a few cases with DNA testing, but a lot of our effort should be focused on educating physicians, gaining the trust of the public in preventive care, and following the guidelines we already have,” says Shamburek.

Articles from Biotechnology Healthcare are provided here courtesy of MediMedia, USA