Putting Into Perspective the Hazards of Untreated Familial Hypercholesterolemia

I n this issue of JAHA, Kjaergaard et al 1 describe a 21-year follow-up of 118 heterozygous carriers of low-density lipoprotein (LDL) receptor (LDLR) mutations causing heterozygous familial hypercholesterolemia (FH) together with 102 of their noncarrier relatives. These FH patients and their relatives had been identified between 1992 and 1994 through cascade screening, starting from LDLR mutation-carrying probands in 32 families. Lipid-lowering treatment with statins was recommended to all mutation-carrying FH participants. Primary outcomes were tracked in the Danish National Patient Registry and included death from any cause, myocardial infarction, coronary revascularization, ischemic stroke, transient ischemic attack, and peripheral artery disease. FH patients and unaffected relatives with occurrence of any of these outcomes prior to the baseline were excluded from the analysis. A set of controls were matched 10:1 by birth year and sex from the Danish Civil Registration System. Despite the vast majority of the FH patients being treated with statins, probably for most of the follow-up period, risk of the primary outcome remained elevated with a hazard ratio 1.65 (95% CI 1.17–2.33). Not unexpectedly, the risk specifically for coronary events was considerably higher among the FH patients (hazard ratio 5.91, 95% CI 3.83–9.10), while no significant excess risk was seen for stroke or total mortality. Indeed, total mortality was somewhat less in FH patients and considerably less in their unaffected relatives, perhaps because of the increased attention to healthy lifestyle these families often display. The strengths of the study include the long-term and comprehensive follow-up together with carefully defined FH cases and unaffected relatives. Limitations are the relatively small size of the cohort as well as incomplete information about lipid-lowering therapy (only available after 2004) and standard coronary risk factors. This study comes on the heels of new recognition of a much higher prevalence of FH than previously appreciated, making it the most common, serious monogenic disorder in humans. New, objective screening projects in large US populations, with genetic testing done without regard to lipid levels, place the prevalence of FH mutation carriers (with mutations in LDLR, APOB, and PCSK9) in 3 different studies at 1 in 204, 1 in 211, and 1 in 222: more than double older estimates of 1 in 500. Similar estimates for prevalence of FH are reported for European populations. Yet, FH remains seriously underdiagnosed and inadequately treated. Risk of premature coronary disease among untreated FH remains of major interest for public health planning and to better appreciate the need for early identification and treatment. Accurate estimates of cumulative risk for coronary artery disease (CAD) by age and sex in untreated FH as compared with non-FH subjects are also of interest for purposes of calculating the likelihood of having FH in a newly developed algorithm for clinical diagnosis of FH. The estimates of cardiovascular disease and CAD incidence and associated hazard ratios by Kjaergaard et al herein are hampered by incompletely documented effects of prior treatment. The same may be said of the several other recent overall estimates of risk associated with genetically defined FH. None of the overall estimates of risk in FH mutation carriers versus noncarriers in these studies should be taken as risk associated with untreated FH. Perhaps the best estimate of risk of CAD in untreated FH in these studies comes from Khera et al, who calculated a hazard ratio of 22.3 (P<0.0001) for CAD among FH mutation carriers with LDL cholesterol (LDL-C) ≥190 mg/dL (compared with a reference group of noncarriers with LDL-C <130 mg/dL). Interestingly, in this study FH mutation carriers had 2to 3-fold higher risk compared with noncarriers at the same current LDL-C levels. Evidence was presented that FH mutation carriers had experienced longer The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the University of Utah, Salt Lake City, UT. Correspondence to: Paul N. Hopkins, MD, MSPH, Cardiovascular Genetics, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Utah, 417 Wakara Way, Room 2124, Salt Lake City, UT 84108. E-mail: paul.hopkins@utah.edu J Am Heart Assoc. 2017;6:e006553. DOI: 10.1161/JAHA.117. 006553. a 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.