Knowing the Prevalence of Familial Hypercholesterolemia Matters
2016; Lippincott Williams & Wilkins; Volume: 133; Issue: 11 Linguagem: Inglês
10.1161/circulationaha.116.021673
ISSN1524-4539
AutoresAnne C. Goldberg, Samuel S. Gidding,
Tópico(s)Diabetes, Cardiovascular Risks, and Lipoproteins
ResumoHomeCirculationVol. 133, No. 11Knowing the Prevalence of Familial Hypercholesterolemia Matters Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBKnowing the Prevalence of Familial Hypercholesterolemia Matters Anne C. Goldberg, MD and Samuel S. Gidding, MD Anne C. GoldbergAnne C. Goldberg From Washington University School of Medicine, St. Louis, MO (A.C.G.); and A. I. DuPont Hospital for Children, Wilmington, DE (S.S.G.). and Samuel S. GiddingSamuel S. Gidding From Washington University School of Medicine, St. Louis, MO (A.C.G.); and A. I. DuPont Hospital for Children, Wilmington, DE (S.S.G.). Originally published15 Mar 2016https://doi.org/10.1161/CIRCULATIONAHA.116.021673Circulation. 2016;133:1054–1057Familial hypercholesterolemia (FH) is a common genetic disorder of cholesterol metabolism that leads to lifetime high low-density lipoprotein cholesterol (LDL-C) levels and markedly increased risk of coronary heart disease (CHD). It is underdiagnosed and undertreated.1,2 Most physicians believe that FH is rare and not often seen in practice. In fact, it is significantly more common than 1:500, the estimate made at the time that Brown and Goldstein identified the LDL receptor. Current studies suggest a prevalence of 1 in 200 to 300 people based on work in the Netherlands, Denmark, and other countries where genetic testing has played a significant role.3,4 There are as many as 34 million people with FH worldwide, with a new person with this condition born every minute.2Article, see p 1067In the article by de Ferranti et al5 in this issue of Circulation, the authors have applied a modified version of diagnostic criteria for FH (the Dutch Lipid Clinics criteria) to a large data set to calculate the prevalence in the United States, with an estimate of 1 in 250 adults, with some variation by ethnicity and caveats related to the limitations of the data source. Given the lack of a national health care system, only emerging registry data, and a general lack of cascade testing, it has been difficult to obtain FH prevalence estimates in the United States.6 These data suggest that ≈1.5 million people in the United States are affected. A high percentage are not diagnosed or treated.Without recognition, FH care cannot be accomplished. The recent American College of Cardiology/American Heart Association clinical practice guideline for cholesterol includes adults with LDL-C >190 mg/dL as a statin benefit group,7 but detailed discussion of FH and other genetic disorders is only in the full report8 (available online but not widely read or cited). Although the benefit of substantial LDL-C lowering on FH outcomes is clear with statins, the published American College of Cardiology/American Heart Association guideline does not emphasize the importance of considering those with FH as separate from population-based recommendations because the long-term risk is substantial.9Before the availability of genetic testing, diagnosing FH began with the identification of a patient with LDL-C at an extreme level with or without CHD, and then finding a first-degree relative with a similar elevation. Scoring systems including MEDPED, the Dutch Lipid Clinics, and the Simon Broome Registry validated by genetic testing have been developed but are imperfect.10 The article by de Ferranti et al5 relied on the Dutch Lipid Clinics algorithm to the extent data could be extracted from the US National Health and Nutrition Examination Survey database.Recognition by some countries of the importance of finding all FH patients in a defined population led to cascade screening to identify family members from confirmed index cases and to improve understanding of the complex relationship among LDL-C, large-effect single-gene defects, and small-effect genes modifying LDL-C levels. There is substantial overlap in LDL-C levels between heterozygotes and homozygotes, and patients with a disproportionately large number of small-effect genes may have LDL-C levels similar to heterozygotes, contributing to diagnostic complexity.11 Unidentified genes may cause FH in patients with negative genetic testing.For these reasons, a recent American Heart Association Scientific Statement advocated for a revised diagnostic classification linking proposed International Classification of Diseases, 10th Revision codes, which allow recognition of FH in the big-data lexicon, to a clinical or phenotypic diagnosis and to genetic diagnosis10 (Table). Further research will be required to validate this new schema, but it provides the advantage of allowing all presenting patients to be classified based on risk (as defined by LDL-C level) and genotype if available. If the International Classification of Diseases, 10th Revision proposed codes are adopted, there will also be a code for those for whom exact classification remains elusive.Table. Familial Hypercholesterolemia Diagnostic CategoriesICD-10 CategoryClinical CriteriaWhen Genetic Testing PerformedHeterozygous familial hypercholesterolemiaLDL-C >160 mg/dL (4 mmol/L) for children and >190 mg/dL (5 mmol/L) for adults and with 1 first-degree relative similarly affected or with premature CAD or with positive genetic testing for an LDL-C–raising gene defect (LDL receptor, apo B, or PCSK9)Presence of 1 abnormal LDL-C raising (LDL receptor, apo B, or PCSK9) gene defectDiagnosed as heterozygous FH if gene raising defect positive and LDL-C 400 mg/dL (10 mmol/L), they should be treated similarly to homozygotesPresence of both abnormal LDL-C–raising (LDL receptor, apo B, or PCSK9) gene defect(s) and LDL-C–lowering gene defect(s) with LDL-C 400 mg/dL (10 mmol/L) and 1 or both parents (a) having clinically diagnosed familial hypercholesterolemia, (b) positive genetic testing for an LDL-C–raising (LDL receptor, apo B, or PCSK9) gene defect, or (c) autosomal recessive FHPresence of 2 identical (true homozygous FH) or nonidentical (compound heterozygous FH) abnormal LDL-C–raising (LDL receptor, apo B, or PCSK9) gene defects; includes the rare autosomal recessive typeIf LDL-C >560 mg/dL (14 mmol/L) or LDL-C >400 mg/dL (10 mmol/L) with (1) aortic valve disease or (2) xanthomata at <20 years of age, homozygous FH highly likelyOccasional homozygotes have LDL-C <400 mg/dL (10 mmol/L)Sitosterolemia, obstructive liver disease, and other causes of secondary hypercholesterolemia should be excludedFamily history of familial hypercholesterolemiaLDL-C level not a criterion; presence of a first-degree relative with confirmed FHGenetic testing not performedapo B indicates apolipoprotein B; CAD, coronary artery disease; FH, familial hypercholesterolemia; ICD-10, International Classification of Diseases, 10th Revision; and LDL-C, low-density lipoprotein cholesterol.Reprinted from Gidding et al10 with permission of the publisher. Copyright © 2015, the American Heart Association.Too many diagnoses are made at the time of the first cardiac event. Rates of premature CHD in adults with FH are manyfold times higher than nonaffected adults, and FH accounts for a high percentage of myocardial infarction before 40 years of age.9 When the first event is fatal, there is no chance for even secondary prevention. Many adults are unlikely to have been screened in childhood and are not screened for FH in their early 20s and 30s, a time when many may not be seeing physicians regularly. Long-term drug therapy has the potential to lower CHD event rates in FH patients to levels similar to those of the general population.12 Treatment is optimally begun at 8 to 10 years of age in heterozygotes and at diagnosis in homozygotes with regular follow-up thereafter.10,13,14 Primordial prevention of nonlipid risk factors can be provided early, before additive effects of the interaction of high LDL-C levels with obesity, tobacco use, and physical inactivity mount up. Cost benefit analyses suggest that substantial savings may accrue with cascade screening and early diagnosis.15,16Effective strategies for treatment of FH begin with lifestyle changes and statins followed by ezetimibe.14,17 Substantial lowering of LDL-C levels is possible in heterozygous FH patients, and the addition of other modalities such as LDL apheresis and new medications can be used for severe heterozygous patients. The PCSK9 monoclonal antibodies, alirocumab and evolocumab, have made it possible to bring LDL-C levels into optimal ranges in patients with FH.18,19 Further ramification of diagnosis for patients is that access to newer drugs such as PCSK9 inhibitors may depend on genetic confirmation of diagnosis and not LDL-C level. Identification of patients with FH is of great importance when payers are making decisions about which patients are primary candidates for new expensive therapies.The work of de Ferranti et al5 highlights the advantages and the pitfalls of big-data analysis with regard to FH. The data set can never have sufficiently reliable data about family history, medication use, or genetic diagnosis to perfectly meet criteria of diagnostic schema such as Simon Broome or the Dutch Lipid clinics. Nor can the data set overcome the limitation created by the age-related rise in LDL-C and the associated decline in sensitivity related to relying solely on LDL-C levels.20 However, the data for those <30 years of age are likely highly accurate and estimate relative prevalence by ethnicity where sample size is sufficient. Knowing an approximate prevalence, hopefully abetted by the introduction of International Classification of Diseases, 10th Revision codes for FH, allows for the consideration of cost analyses that might evaluate screening strategies to identify more individuals and demonstrates the ability of a big-data pull to identify possible index cases and thus initiate cascade screening.21The National Lipid Association focused attention on the importance of FH in its 2011 report on the disease, and the International and European Atherosclerosis Statements have defined the current status of FH care internationally.2,13,14,22 The recent American Heart Association scientific statement has identified issues that must be addressed in the next decade of FH care.10 The work of De Ferranti et al determines the approximate prevalence of FH in the United States.5 We have reached a threshold in the care of FH for the United States. We know the genetic condition and its health implications, and we know the approximate prevalence. We now need to provide state-of-the-art care to prevent the CHD it causes.DisclosuresDr Goldberg receives consulting fees from Sanofi/Regeneron and OptumRx, research grant support from Amarin, Merck, ISIS, Sanofi-Aventis, Regeneron, Amgen, Pfizer, Genentech/Roche, and Glaxo-Smith-Kline, and honoraria for editorial work on the Merck Manual. She serves on the Board of the Foundation of the National Lipid Association and on committees of the National Lipid Association and of the American Heart Association. Dr Gidding is a member of the scientific advisory board and publication committees of the FH Foundation. He has received honoraria from the American College of Cardiology for producing FH-related educational materials.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Samuel S. 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Watts G, Ding P, George P, Hagger M, Hu M, Lin J, Khoo K, Marais A, Miida T, Nawawi H, Pang J, Park J, Gonzalez-Santos L, Su T, Truong T, Santos R, Soran H, Yamashita S and Tomlinson B (2016) Translational Research for Improving the Care of Familial Hypercholesterolemia: The "Ten Countries Study" and Beyond, Journal of Atherosclerosis and Thrombosis, 10.5551/jat.35949, 23:8, (891-900), . March 15, 2016Vol 133, Issue 11 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.116.021673PMID: 26976913 Originally publishedMarch 15, 2016 Keywordscongenitalhyperlipoproteinemia type IIheart defectsprevention & controlcholesterolEditorialsPDF download Advertisement SubjectsCardiovascular DiseasePrimary PreventionRisk Factors
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