SNOWMASS, COLO. – Familial hypercholesterolemia (FH), the most common genetic cause of premature atherosclerotic cardiovascular disease, affects an estimated 1 in 250 Americans. It doesn’t help that physicians are doing a terrible job of finding and treating them, Robert A. Vogel, MD, said at the Annual Cardiovascular Conference at Snowmass.
Indeed, it’s estimated that U.S. physicians diagnose fewer than 1% of affected individuals, as compared with a world’s-best 71% rate in the Netherlands, 43% in Norway, 13% in Sweden, and 12% in the United Kingdom (Eur Heart J. 2013 Dec 1;34[45]:3478-90a).
Dr. Robert A. Vogel
“You all have patients with FH in your practices. You have the parents, who already have atherosclerotic cardiovascular disease, but the kids need to be identified as well. Nothing is as gratifying as preventing disease in someone who would suffer a stroke or MI in the future,” the cardiologist continued.
FH is present in 7.5% of men and fully 11.1% of women with coronary heart disease (CHD), according to an analysis of more than 7,000 CHD patients in the EUROASPIRE IV study (Atherosclerosis. 2015 Jul;241[1]:169-75). Swiss investigators have shown, in a prospective study of 4,534 patients with acute coronary syndrome, that those who have FH are at significantly greater 1-year risk of recurrent fatal and nonfatal coronary events (Circulation. 2016 Sep 6;134[10]:698-709).
“You’re going to do worse after an MI if you have FH. These are very-high-risk folks. We need to find them because treatment is effective,” Dr. Vogel emphasized.
Three different sets of diagnostic criteria are available for FH: the Dutch Lipid Clinic Network diagnostic criteria, the Simon Broome criteria, and most recently, the American Heart Association criteria (Circulation. 2015 Dec 1;132[22]:2167-92).
There are common themes among the three sets of diagnostic criteria: Think FH when you encounter an LDL cholesterol level greater than 190 mg/dL in a patient not on statin therapy or more than 130 mg/dL on statin therapy, a personal or family history of premature atherosclerotic cardiovascular disease, or a patient with the characteristic findings of FH on physical examination.
These characteristic physical findings are xanthelasmas, corneal arcus, tuberous xanthomas, and Achilles tendon xanthomas, which Dr. Vogel called “the sine qua non of FH.”
The importance of tendon xanthomas as a manifestation of FH is vividly illustrated in the Dutch diagnostic criteria. Under the Dutch points-based scheme, various numbers of points are given for LDL level; a personal or family history of premature CAD, peripheral vascular disease, or stroke; positive physical findings; and a genetic test positive for a functional mutation in the LDL receptor gene. “Definite FH” requires a total of more than eight points, and a finding of tendon xanthomas alone provides six of them.
Tendon xanthomas are not only a key diagnostic feature, they are also important prognostically. They indicate that a patient is going to do relatively worse, independent of LDL level or LDL receptor gene mutation status (Arterioscler Thromb Vasc Biol. 2005 Sep;25[9]:1960-5).
A genetic test isn’t needed most of the time to diagnose FH, but it’s nevertheless helpful because it provides specific information about the patient’s LDL receptor status. A patient with a receptor-negative mutation in the LDL receptor gene is going to be much less responsive to maximum-intensity statin therapy than if defective LDL receptors are present.
Another test well worth ordering in a patient with FH is a lipoprotein(a) measurement. As shown in the prospective SAFEHEART trial (Spanish Familial Hypercholesterolemia Cohort Study), lipoprotein(a) is an independent predictor of cardiovascular disease in both men and women with FH. The risk is highest in those with lipoprotein(a) above 50 mg/dL – a normal level is below 30 mg/dL – who carry a null mutation in the LDL receptor gene (J Am Coll Cardiol. 2014 May 20;63[19]:1982-9).
Dr. Vogel reported serving as U.S. national coordinator for the ongoing ODYSSEY trial of the PCSK9 inhibitor alirocumab for cardiovascular risk reduction.