This editorial by Dr. Baum was originally published in the Journal of Clinical Lipidology, Vol 8, No 6, December 2014 and re-published with permission.
“The demands of this poor public are not reasonable, but they are quite simple. It dreads disease and desires to be protected against it. But it is poor and wants to be protected cheaply. Scientific measures are too hard to understand, too costly, too clearly tending towards a rise in the rates and more public interference with the insanitary, because insufficiently financed, private house. What the public wants, therefore, is a cheap magic charm to prevent, and a cheap pill or potion to cure, all disease. It forces all such charms on the doctors.”
George Bernard Shaw THE DOCTOR’S DILEMMA: PREFACE ON DOCTORS (1909).
Scientific progress and the tower of babel
Many may have forgotten that Goldstein and Brown originally ascribed familial hypercholesterolemia (FH) to defective 3-hydroxy-3-methyl-glutaryl coenzyme A reductase.(1) The authors promptly corrected their proposition and concluded that a defect in the low-density lipo- protein (LDL) receptor was the basis of FH.(2) Although they had initially been incorrect, their mistake simply illustrated the norm in scientific discovery—and, they won the Nobel Prize in Medicine. Theories are proposed and tested; understanding is honed; and new theories are rewritten. Such iteration is at the heart of progress in science. And, it is a process in need of application by healthcare practitioners worldwide to improve the detection and treatment of people with FH. Specifically, today’s lexicon for FH has evolved to the point of clinical incomprehension.(3,4) Its complexities, ambiguities, and embedded misnomers (e.g., How can double or compound heterozygotes be homozygotes?) will often pose confusion, paradox, and dilemma for the clinician sufficient to impair clinical care; clarification is therefore required.(5–8)
Brief historical perspective
FH was originally defined as a life-threatening auto- somal-dominant, monogenic mutation of the LDL receptor that resulted in hypocatabolism of LDL particles and premature atherosclerosis.(9) Goldstein’s and Brown’s early interpretation of patient data and their use of the Hardy-Weinberg equation for monogenic disorders led to the long held dictum that homozygous FH (HoFH) occurs at a rate of 1 per 1 million, whereas heterozygous FH (HeFH), 1 per 500.(9–11) Unbeknownst to them at the time of their discovery, their scientifically precise definition of the prevalence of HoFH possessed inherent limitations, because it referred strictly to only those patients with a single and same mutation in the LDL receptor inherited from both parents. Now we have come to recognize great phenotypic variability in FH,(12) the worst phenotype being homo- zygous FH determined by the presence of two null alleles in the LDL receptor. Consanguinity additionally enhances the severity of HoFH as evidenced by the founder effects across the world.(10,11) And, many other mutations outside the LDL receptor can also lead to FH.(3,4,11,12)
Evolution of a definition
“HoFH is an infrequent inherited disorder usually caused by mutations in both LDL receptor alleles, which results in very high elevated plasma LDL cholesterol concentrations and very early morbidity and mortality due to accelerated atherosclerotic cardiovascular disease (ASCVD), usually before the patient turns 30 years old. In patients with HoFH, the main cause of mortality and morbidity is the aortic stenosis rather than involvement of the coronary arteries.”(9) This was an original definition for HoFH written by the “fathers” of the disorder. This, as well as the original molecular definition, has itself mutated over the years. FH now includes autosomal dominant mutations in at least two other genes, PCSK9 and apoB 100.(3,4) To further confuse the issue, molecularly defined HoFH now includes both double heterozygotes and compound heterozygotes and may also rarely involve more than two mutations.(10,11) Double heterozygotes possess mutations in two of the aforementioned genes, whereas compound heterozygotes have two different mutations in one of the afore-mentioned genes. Strictly speaking, neither of these entities represents true homozygosity, yet clinically they do result in an HoFH phenotype, albeit with varying penetrance of LDL levels and consequent atherosclerotic cardiovascular disease (ASCVD). For this reason, the newer and less genetically precise terms have appropriately become embedded in our definition of HoFH. This expanded HoFH definition enables doctors to broaden their detection and care of such patients, an extraordinarily high-risk population in need of early and aggressive treatment.13,14 Markedly elevated plasma LDL cholesterol (LDL-C) levels exist even in utero, emphasizing both the genetic nature and very high lifetime risk of ASCVD risk of FH (Fig. 1).(15) Beyond our genetic redefinition of FH, we now recognize the disorder to perturb the entire lipoprotein system.(16) From a metabolic perspective, there is more than just reduced clearance of LDL; there is also coexistent overproduction of apoB, undercatabolism of remnant lipoproteins, and dysfunction of HDL.(16) These extended abnormalities are, however, embedded in the extent of residual LDL re- ceptor activity, which from a metabolic viewpoint could potentially be used to further define FH; however, such molecular testing is not yet readily accessible.(10) As a consequence of the aforementioned diagnostic ambiguities, physicians around the world often face artificial and inappropriate obstacles to optimally manage their patients with HoFH. In the United States, the use of novel agents—lomitapide and mipomersen—are restricted to clinically defined HoFH patients.(17–19) In most countries outside the United States, the United Kingdom, Spain, Japan, and Germany, the use of lipoprotein apheresis is not reimbursed, but if it is, a restricted definition of HoFH is required.(9,10) To enable clinicians to better treat their patients, an improved and pragmatic definition is required for the highest risk FH patients.
Fig. 1 Threshold for ASCVD as a function of cumulative LDL-C exposure. This adaptation emphasizes the genetic aspect of FH, bringing the start point of LDL-C accumulation into the in utero period. Exposure to markedly elevated LDL-C levels occurs even before birth, further explaining the prematurity of ASCVD in such individuals. Additionally the figure introduces the suggested terminology, ‘‘very high-risk’’ and ‘‘high-risk’’ FH. Adapted from Horton JD, et al. J Lipid Res. 2009; 50 (Suppl):S172-S177.
Revision of earlier concepts
Over the past few years, it has become apparent that the current definition of HoFH (expanded from its origi- nal Goldstein and Brown view) is likely inadequate.(11,12) We now have evidence that the prevalence of HoFH may be one in 160,000,(12) whereas HeFH occurs somewhere between 1 in 200 and 1 in 300.(20,21) As noted previously, it is clear that three genes—LDL receptor, PCSK9, and apoB100—mutate and lead to the preponderance of FH cases.(3,4,7,8) There remain some important caveats, however. These estimates of prevalence actually exclude double heterozygotes as well as any potential de novo LDL receptor mutations. Moreover, the new prevalence calculations are approximate estimates of frequencies(12) not being calculated according a multilocus variant of the Hardy- Weinberg principle(22) and without considering population admixture. Additionally, phenotypic analyses in the Copenhagen study show a remarkably large number of patients with severe hypercholesterolemia.(20) It is not clear if this is the result of sharing an unhealthful diet or a high prevalence of inherited disorders, which would suggest genetic isolation.
With regard to double heterozygotes, although the expectation is for them to represent only 5% of the HoFH population, their prevalence in the largest study of geno- typed patients to date was the same as that of compound heterozygotes.(12) Double heterozygotes were removed however from prevalence statistics because such individuals possess a polygenic disorder (two genes to be precise). The authors therefore considered them to be unevaluable by Hardy-Weinberg.(12,22) However, a multilocus Hardy-Weinberg calculation could be performed, bringing a greater precision to the authors’ findings as well as our current understanding of FH prevalence.(12) Because the prevalence of double heterozygotes was much greater than anticipated, and as polygenic mutations are known to remain stable over generations, it is probably inaccurate to exclude these double heterozygotes from Hardy-Weinberg analysis. By doing so, we are left with prevalence estimates that fail to account for double heterozygotes with phenotypic or clinical HoFH.(3,4,23)
There is also the issue of typically requiring both parents to have either very high LDL or premature ASCVD to meet clinical HoFH criteria.(10,11) Two notions could argue against this requirement. First, there is the possibility of de novo mutations. Although little is known specifically about the incidence of de novo LDL receptor gene variants, we do know that this gene can be subject to many mutations.(4)
Recently, whole exome sequencing for the evaluation of other Mendelian disorders revealed a surprisingly high incidence of 83% de novo mutations in autosomal dominant disorders in the population assessed.(23) More than 1700 genetic variants in the LDL receptor have hitherto been identified (not all of which are pathogenic, however). Such a high prevalence of mutations in the LDL receptor does raise the question of whether or not it can also be subject to de novo mutations.(7,23) Second is the issue of nonpaternity, a very challenging matter in a clinical setting.(8) Nonpaternity occurs when the presumed father of a child is not the biological father and is rather frequent with estimates between 0.8 and 30%.(24) Further confounding the assessment of true HoFH is the fact that genotyping itself, probably owing to technical limitations in the main, is imperfect. It is far less sensitive than we would like. Estimates are that somewhere between 20% and 70% of patients manifesting as phenotypic or clinical possible to definite FH (HeFH and HoFH) can be overlooked through current genetic sequencing techniques.(7,8,25–27)
Communities subject to gene founder effects aside,(23) it therefore appears that the figures cited previously for the population prevalence most likely underestimate the true frequency of HoFH. HoFH, as expressed clinically, is therefore not only far more common than we previously considered, but it could be even more common than we are presently led to believe. Making matters more perplexing, we now have documentation of pathogenic mutations causing HoFH yet resulting in an untreated LDL-C as low as 170 mg/dL.(12) Such a low LDL challenges prior criteria for HoFH, many of which stipulated an untreated LDL-C .450 mg/dL (and treated LDL-C .300 mg/dL) in the HoFH individual.(10) An untreated LDL-C of 170 mg/dL not only breaches the current HeFH boundaries, but even overlaps with polygenic or common hypercholesterolemia (Fig. 2). Contributing to current scientific uncertainty and clinical ambiguity, polygenic mutations can sufficiently elevate plasma LDL-C to mimic FH.(26,28) Given the emerging new knowledge of the prevalence, phenotypic expression, and genetic etiology of FH, coupled with the recognition of our inability to clinically and even genotypically distinguish the heterozygous and homozygous entities, why make an arbitrary distinction between HeFH and HoFH?(10–12) We currently do not have the capacity to be scientifically precise in making this distinction. Therefore, from a practical perspective, we must either revise our definition of HoFH, or abandon the notion that such a definition should take a primary position in the clinical decision making process. Because a clinically pragmatic revision of the definition will only take us further from the true genetic meaning of the term, it might be best simply to acknowledge that the definitions of HoFH or HeFH should have a diminished role in the clinical management of patients after the diagnosis of FH has been made. Our view is that the phenotypic expression of the disease should drive the patient-centered therapeutic strategy.
Fig. 2 Low-density lipoprotein-cholesterol levels in homozygous autosomal dominant hypercholesterolemia patients prior and after LLT. Plus indicates patients with two null alleles. Open diamond indicates patients with one null allele and one defective allele. Closed square indicates patients with two defective alleles. Horizontal lines indicate mean LDL-C levels. Statin-naive LDL-C levels were available for 32 homozygous autosomal dominant hypercholesterolemia patients. Treated LDL-C levels were avail-able for 43 homozygous autosomal dominant hypercholesterolemia patients. LLT, lipid-lowering therapy. Reprinted with permission from the European Heart Journal. Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype–phenotype relationship, and clinical outcome. Eur Heart J. 2014:ehu058.
Meeting the challenge with a clinical solution: improving the utilization of novel therapiesBy early 2013, two novel agents, lomitapide and mipomersen, were approved in the United States as adjunctive therapies for patients with HoFH aged $18 years.(19,29) Because HoFH is by definition an orphan or rare disease (affecting fewer than 200,000 people in the United States, or less than 1 in 1500), the Food and Drug Administration’s evaluation of these medications differed substantially from their standard pharmaceutical approval process. Additionally, orphan medications are exceedingly expensive, often more than $200,000 per patient per year. Thus, to prescribe these medications, physicians must attest that the patients for whom they are prescribing the drug meet the criteria for the given rare disease, in this case HoFH. Specifically, a prescribing doctor must state, ‘‘I affirm that my patient has a clinical or laboratory diagnosis consistent with HoFH’’.(29) In other words, a necessary barrier has been constructed to prescribing orphan drugs. Herein lies the specific major issue though. As argued previously, the demarcation between HeFH and HoFH can be challenging on both clinical and genetic grounds. Consequently,FH—including HoFH—is grossly underdiagnosed and similarly undertreated. It is estimated that less than 1% of FH patients in the United States have been adequately diagnosed.(7) Reeducation is in order; teaching medical practitioners to have FH as a fixture on their differential diagnostic list of LDL disorders is crucial.(5–8) Equally pressing, however, and of immediate concern in the United States, is the quandary of when to prescribe these novel medications to our patients, acknowledging also the lack of clinical endpoint trials, which for ethical reasons will never be undertaken.(19) It would be simple if the issue were clear-cut. This is far from the case, however, and can present the treating physician with a challenging clinical dilemma. Doctors must acknowledge the difficulties inherent in distinguishing HeFH from HoFH, but still determine whether a given patient presents with a clinical phenotype that is consistent with HoFH. Because FH can be a lethal condition in either heterozygous or homozygous forms our approach should be driven by the clinical manifestations of an individual patient’s specific, causative molecular or genetic defect.
The doctor’s dilemma resolved with a common language strategy: a pragmatic approach to managing clinically severe FH
We proffer the following clinically grounded approach that may simplify and enhance the care of adult patients with clinically severe FH, regardless of its genetic bases (Fig. 3).
Triage using established clinical tools
A family history of premature vascular disease, a marked and often isolated elevation of LDL-C, premature and/or aggressive vascular disease, a limited response to lipid-lowering therapy, and the presence of physical stigmata of FH must all be considered.(5–8) If, based on these considerations, there is a strong suspicion of FH, either the Simon Broome or the Dutch Lipid Clinic Network criteria should be employed.(5–8) Worldwide, the Dutch Lipid Clinic is more commonly used because it is considered more sensitive than Simon Broome.(7,8) Although it is commonly considered the system of choice to help clinicians diagnose FH (7,8) in Western populations, in other countries alternative criteria should be employed.(21,30) MEDPED is excluded here because its system hinges solely upon LDL-C levels and strictly requires knowing LDL-C in several family members.(31) In our opinion, this tool also bears ambiguities that may be confusing when cascade screening to detect new family members with FH. It is important for clinicians to recognize that LDL-C levels differ between the sexes and steadily rise through life.
Fig. 3 Novel care pathway for identifying and treating patients with FH. In view of the recently recognized wide genetic and phenotypic variability of FH, this algorithm is intended to simplify and improve care of patients with this disorder. The algorithm shifts the impetus of therapeutic intervention choices from genetics to phenotypic/clinical expression. The individual patient with his or her unique manifestation of disease is emphasized.
Thus, an LDL-C adjustment should be contemplated when calculating the likelihood of FH, particularly when there is a family member with documented FH.(32) If patients do not meet FH criteria when assessed with the Dutch Lipid Clinic Network, they should be treated according to current lipid and cholesterol guidelines.(33–36)
Assessing ASCVD and an inadequate response to treatment
With severe/progressive ASCVD, or a clinically significant degree of subclinical disease, and probable or definite FH,(7,8) the patient could be considered to have a condition termed ‘‘high-risk FH.’’ Every effort using standard therapies should then be made to drive the LDL-C below 70 mg/dL.(6–8) Lipoprotein a (Lp(a)) should also be assessed.(37) Lp(a) is a potent, independent risk factor for coronary events in FH and an assessment of its plasma concentration and allelic size therefore has been incorporated into this protocol.(38) Very high plasma Lp(a) concentrations may mandate earlier introduction of lipoprotein apheresis (39–41) or, when available, apolipoprotein a antisense therapy.(16) If the level is $50 mg/dL, regardless of the LDL-C level, lipoprotein apheresis should be initiated. If an aggressive attempt to reach an LDL goal ,70 mg/dL is unsuccessful, the patient should be considered to have ‘‘very high-risk FH.’’(42) This classification would emphasize the urgency and concomitantly augment the intensity of treatment. Although ‘‘very high-risk FH’’ might include both patients with severe HeFH as well as those with severe HoFH, the US Food and Drug Administration attestation for the two novel agents lomitapide and mipomersen (17,18) could be satisfied on clinical grounds. Such a classification system is reasonable given our recent understanding of the greatly overlapping spectra of HeFH and HoFH. Both lipoprotein apheresis and/or these novel medications must be seriously considered in very high-risk individuals with FH. As further evidence for the efficacy and safety of PCSK9 inhibitors in severe FH grows and other therapies,(18,43,44) such as the CETP inhibitors, potentially achieve their clinical endpoints, the algorithm may be applied to these agents as well.(11)
Managing the FH patient free from ASCVD
In the absence of significant vascular disease (e.g., prior ASCVD event; peripheral artery disease; obstructive carotid artery disease; coronary artery calcification $75% forage/sex; coronary artery calcification $300; or a large burden of soft plaque or multiple plaques noted on coronary computed tomography angiography), the patient should be managed aggressively with conventional approaches, including therapeutic lifestyle changes.(7,8,34) Follow-up evaluation with imaging studies is recommended. The review intervals should be determined on clinical grounds, perhaps ranging from every other year to every 5 years. The frequency of imaging will depend on the severity of the patient’s residual LDL-C elevation as well as the initial degree of any vascular disease.(11,45,46) The key is to very aggressively manage those FH patients with poor prognostic indicators. Comorbidities such as tobacco abuse, hypertension, diabetes mellitus, and a markedly elevated Lp(a) should also be aggressively treated when possible.(7,8,11,33–37)
Reflections on the algorithm
At present, physicians must accept our inability to be certain of the exact genetic etiology of FH in patients in whom they have made a well-considered clinical diagnosis of the condition. Likewise, physicians practicing in the United States must not fear the attestation required to prescribe the aforementioned novel medications for FH. This is not a proclamation of the incontestability of the diagnosis of HoFH. The attestation simply states that HoFH remains solidly on the differential diagnostic list. The pragmatic solution that we propose is likely to widen use of novel medications and lipoprotein apheresis. However, their enhanced use is compatible with best clinical care for a condition that inadequately treated bears a uniquely high risk of ASCVD.(13,14,47)
It is also true that ASCVD outcome studies have not been performed with these novel agents, and their long-term safety has yet to be demonstrated.(19,48) Still, it is reasonable to infer emergent significant risk reduction when this highly at-risk population experiences LDL-C reductions of 25 –50% and greater.(8,11,13,14) Additionally, the proposed algorithm could be readily tested with large cohorts of FH patients, for instance within the context of national and international registries.(49,50) For example, patients defined in the proposed clinical algorithm should be incorporated into the ongoing registry, CASCADE FH. Through CASCADE FH, real-world cost/benefit analyses will become possible. Though the cost of more prevalent drug therapy and lipoprotein apheresis would be problematic, it is not unreasonable to assume that the increased use and effectiveness of these therapies could concomitantly drive down their costs. Included in such a cost analysis (which is beyond the scope of this article) must also be considerations regarding the costs averted by the prevention of ASCVD as well as the improved quality of life from prevention of clinical events and indirect cost savings to society.(13,14,51,52)
A biochemical distinction that may bear on the response to new therapies, particularly with PCSK9 inhibitors,(43,48) has been previously made among patients with severe FH on the basis of residual LDL-receptor functional activity measured in skin fibroblasts.(53) The notion of including such a measurement in the clinical assessment and triaging of patients has appeal, but the technical complexities restrict its application to research settings alone. Additionally, the skin fibroblast, having no role in maintaining our body’s cholesterol homeostasis, may not be the best model on which we should base clinical decisions. Plasma PCSK9 levels vary with LDL-C concentrations,(54) but whether this measurement has a role with clinical management of patients remains unclear.
Finally, the algorithm does not include children, but in this age group the diagnosis of ‘‘high-or very high-risk FH’’ may also be readily made on clinical grounds.(8,10,11) Guidelines recommend that all children with suspected FH be screened with measurement of LDL-C with or without a test for the family mutation, if known, by age 2 years and treated aggressively, including as indicated lipoprotein apheresis, by age 5 years and no later than 8 years.(8,11) There is very limited experience with the new therapies for lowering LDL-C in children. However, children deemed to have high risk FH could enter the algorithm at the stage of confirming subclinical ASCVD and/or aortic valve disease.(8,11)
Baum Challenges in HFH diagnosis and care
So is there a role for genetic testing in the care of FH?
The detection and management of FH includes the entire family. Cascade screening of close family members is part of our duty of care and, resources permitting, this is where there is an important role for genetically testing of index cases to identify the pathogenic mutation/s causative of FH.(5,8,55)
Genetic testing is most unlikely to alter the management of the index case once the clinical diagnosis has been made, but it can certainly make cascade screening more cost-effective and can especially increase the accuracy of diagnosis in children.(52,56–58) The treatment of severe FH in children, although outside the scope of this article, needs to be addressed along similar lines as the pre- sent proposal.(8,11,15,59,60)
Conclusion: enhancing the model of care for severe FH
The physician’s role is to offer each and every patient the best possible standard of care. This is the foundation of the modern era of patient-centered medicine. Instead of grappling with a diagnostic distinction we currently clearly cannot resolve, the time is ripe to focus attention on detecting and appropriately treating the entire spectrum of FH patients in dire need of current best standard of care. Risk stratification and identification of the most severe of these patients should be based on their phenotypic, not genotypic diagnosis, although a genetic diagnosis may be useful in cascade screening families. Patients who have ‘‘high-risk FH’’ or ‘‘very high-risk FH’’ are at extremely high peril of progressive and life-threatening ASCVD. Recalling the adage that inspired an accelerated speed of treatment during the early thrombolytic days, ‘‘time is muscle,’’ we now can use a comparable dictum for this type of FH patient. These individuals share time urgency. Most definitely for them, “time is plaque.”
Future considerations also include the following: improved biochemical typing of the severity of FH and the response to therapy, such as PCSK9 inhibitors, would require the development of simple, precise, accurate and practicable methods for assessing residual LDL-receptor function. Novel imaging methods for detecting inflammation in unstable coronary plaques (61,62) as well as genetic tests to assess individual susceptibility to the side effects of existing (63) and new therapies for FH could in the future be incorporated into the clinical care pathway.
Finally, the algorithm presented is based on our own personal experience of managing caseloads of patients with severe FH who have presented us with clinical challenges and dilemmas. We acknowledge that the proposition is based on expert opinion and therefore constitutes a view- point that requires future testing. It should also be noted however that all guidelines concerning management of HoFH are mainly based on expert opinion (European Atherosclerosis Society/European Society of Cardiology; National Lipid Association; American Hospital Associa- tion/American College of Cardiology; National Institute for Health and Care Excellence; International Familial Hyper- cholesterolemia Foundation). We have remained within current guidelines for FH diagnosis and expanded our therapies in response to our growing understanding of the wide range of FH phenotypic expression as well as clinical predictors of higher risk. The care pathway proposed is a nonprescriptive living document, and as such will need to be investigated and further evaluated, including assessing its effectiveness, utility, and cost-benefit. This is necessary to revise and enhance the protocol and to also allow the incorporation of novel diagnostic and therapeutic capabilities referred to previously that need evaluation in their own right. The algorithm, however, offers clinicians a simplified and pragmatic pathway for more effectively managing high-risk FH patients and lays a new foundation for improvements in international models of care for FH.
Seth J. Baum, MD
University of Miami Miller School of Medicine Miami, Florida E-mail address: firstname.lastname@example.org
E.J.G. Sijbrands, MD, PhD
Department of Internal Medicine Erasmus MC Rotterdam, The Netherlands
Pedro Mata, MD, PhD
Fundacion Hipercolesterolemia Familiar Madrid, Spain
Gerald F. Watts, DSc, PhD, MD
Lipid Disorders Clinic Cardiovascular Medicine Royal Perth Hospital School of Medicine and Pharmacology University of Western Australia, Australia
1. Goldstein JL, Brown MS. Familial hypercholesterolemia: identifica- tion of a defect in the regulation of 3-hydroxy-3-methylglutaryl coen- zyme A reductase activity associated with overproduction of cholesterol. Proc Natl Acad Sci U S A. 1973;70:2804–2808.
2. Brown MS, Goldstein JL. Familial hypercholesterolemia: defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Proc Natl Acad Sci U S A. 1974;71:788–792.
3. Soutar AK, Naoumova RP. Mechanisms of Disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med. 2007; 4:214–225.
4. Usifo E, Leigh SEA, Whittall RA, et al. Low-Density Lipoprotein Re- ceptor Gene Familial Hypercholesterolemia Variant Database: Update and Pathological Assessment. Ann Hum Genet. 2012;76:387–401.
5. National Institute for Health and Clinical Excellence, The National Collaborating Centre for Primary Care. NICE Clinical Guideline 71: Identification and management of familial hypercholesterolaemia. 2008.
6. Goldberg AC, Hopkins PN, Toth PP, et al. Familial Hypercholesterole- mia: Screening, diagnosis and management of pediatric and adult pa- tients: Clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5: 133–140.
7. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hyper- cholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease Consensus Statement of the European Atherosclerosis Society. Eur Heart J. 2013;34:3478–3490.
8. Watts GF, Gidding S, Wierzbicki AS, et al. Integrated Guidance on the Care of Familial Hypercholesterolaemia from the International FH Foundation. Int J Cardiol. 2014;171:309–325.
9. Goldstein JL, Hobbs HH, Brown MS. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill Information Ser- vices Company; 2001.
10. Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: Cur- rent perspectives on diagnosis and treatment. Atherosclerosis. 2012; 223:262–268.
11. Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the Euro- pean Atherosclerosis Society. Eur Heart J. 2014;35:2146–2157.
12. Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal domi- nant hypercholesterolaemia in the Netherlands: prevalence, genotype– phenotype relationship, and clinical outcome. Eur Heart J. 2014.
13. Raal FJ, Pilcher GJ, Panz VR, et al. Reduction in Mortality in Subjects With Homozygous Familial Hypercholesterolemia Associated With Advances in Lipid-Lowering Therapy. Circulation. 2011;124: 2202–2207.
14. Kolansky DM, Cuchel M, Clark BJ, et al. Longitudinal evaluation and assessment of cardiovascular disease in patients with homozygous familial hypercholesterolemia. Am J Cardiol. 2008;102:1438–1443.
15. Vuorio A, Doherty KF, Humphries SE, Kuoppala J, Kovanen PT. Statin treatment of children with familial hypercholesterolemia – trying to balance incomplete evidence of long-term safety and clinical accountability: are we approaching a consensus? Atherosclerosis. 2013;226:315–320.
16. Ooi EMM, Barrett PHR, Watts GF. The extended abnormalities in lipoprotein metabolism in familial hypercholesterolemia: Developing a new framework for future therapies. Int J Cardiol. 2013;168: 1811–1818.
17. Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2013;381:40–46.
18. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a rando- mised, double-blind, placebo-controlled trial. Lancet. 2010;375: 998–1006.
19. Rader DJ, Kastelein JJP. Lomitapide and Mipomersen: Two First-in- Class Drugs for Reducing Low-Density Lipoprotein Cholesterol in Pa- tients With Homozygous Familial Hypercholesterolemia. Circulation. 2014;129:1022–1032.
20. Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG. Familial Hypercholesterolemia in the Danish General Population: Prevalence, Coronary Artery Disease, and Cholesterol-Lowering Medication. J Clin Endocrinol Metab. 2012;97:3956–3964.
21. Shi Z, Yuan B, Zhao D, Taylor AW, Lin J, Watts GF. Familial hyper- cholesterolemia in China: Prevalence and evidence of underdetection and undertreatment in a community population. Int J Cardiol. 2014; 174:834–836.
22. Stern C. The Hardy-Weinberg law. Science. 1943;97:137–138.
23. Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med. 2013;369:
24. Bellis MA, Hughes K, Hughes S, Ashton JR. Measuring paternal discrepancy and its public health consequences. J Epidemiol Commu- nity Health. 2005;59:749–754.
25. Hopkins PN, Toth PP, Ballantyne CM, Rader DJ. Familial Hypercho- lesterolemias: Prevalence, genetics, diagnosis and screening recom- mendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S9–S17.
26. Futema M, Plagnol V, Li K, et al. Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations. J Med Genet. 2014;51:537–544.
27. Norsworthy PJ, Vandrovcova J, Thomas ER, et al. Targeted genetic testing for familial hypercholesterolaemia using next gen- eration sequencing: a population-based study. BMC Med Genet. 2014;15:70.
28. Talmud PJ, Shah S, Whittall R, et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lan- cet. 2013;381:13–19.
29. Food and Drug Administration (FDA). Postmarket Drug Safety Infor- mation for Patients and Providers – JUXTAPID (lomitapide). Food and Drug Administration (FDA); 2013.
30. Harada-Shiba M, Arai H, Oikawa S, et al. Guidelines for the manage- ment of familial hypercholesterolemia. J Atheroscler Thromb. 2012; 19:1043–1060.
31. Williams R, Hunt S, Schumacher M, et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol. 1993;72:171–176.
32. Starr B, Hadfield G, Hutton BA, et al. Development of sensitive and specific age-and gender-specific low-density lipoprotein cholesterol cutoffs for diagnosis of first-degree relatives with familial hypercho- lesterolaemia in cascade testing. Clin Chem Lab Med. 2008;46: 791–803.
33. National Cholesterol Education Program (NCEP). 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) Final Report. Circulation. 2002; 106:3143–3421.
34. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Athero- sclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S1–S45.
35. Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias. Eur. Heart J. 2011;32:1769–1818. 36. Maki KC, Ridker PM, Brown WV, Grundy SM, Sattar N. An assess- ment by the Statin Diabetes Safety Task Force: 2014 update. J Clin
37. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a
cardiovascular risk factor: current status. Eur Heart J. 2010;31:
38. Alonso R, Andres E, Mata N, et al. Lipoprotein (a) levels in Familial
Hipercholesterolaemia: an important predictor for cardiovascular dis- ease independent of the type of LDL-receptor mutation. J Am Coll Cardiol. 2014;63:1982–1989.
39. Leebmann J, Roseler E, Julius U, et al. Lipoprotein Apheresis in Patients with Maximally Tolerated Lipid Lowering Therapy, Lp(a)- Hyperlipoproteinemia and Progressive Cardiovascular Disease: Prospective Observational Multicenter Study. Circulation. 2013;128: 2567–2576.
40. Schettler V, Neumann CL, Hulpke-Wette M, Hagenah GC, Schulz EG, Wieland E. Current view: indications for extracorporeal lipid apheresis treatment. Clin Res Cardiol Suppl. 2012;7:15–19.
41. Thompson GR. The evidence-base for the efficacy of lipoprotein apheresis in combating cardiovascular disease. Atheroscler Suppl. 2013;14:67–70.
42. Thompson GR, Catapano A, Saheb S, et al. Severe hypercholestero- laemia: therapeutic goals and eligibility criteria for LDL apheresis in Europe. Curr Opin Lipidol. 2010;21:492–498.
43. Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal FJ. Ef- fect of the PCSK9 Monoclonal Antibody, AMG 145, in Homozygous Familial Hypercholesterolemia. Circulation. 2013;128:2113–2120.
44. Raal F, Honarpour N, Blom D, et al. Trial evaluating evolocumab, a PCSK9 antibody in patients with homozygous FH (TESLA): Results of the randomised, double-blind placebo-controlled trial. EAS Madrid. 2014 Abstract 1177.
45. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2010;122:2748–2764.
46. Neefjes LA, Ten Kate G-JR, Rossi A, et al. CT coronary plaque burden in asymptomatic patients with familial hypercholesterolaemia. Heart. 2011;97:1151–1157.
47. Versmissen J, Oosterveer DM, Yazdanpanah M, et al. Efficacy of sta- tins in familial hypercholesterolaemia: a long term cohort study. Br Med J. 2008;337:a2423.
48. Page MM, Bell DA, Hooper AJ, Watts GF, Burnett DJR. Lipoprotein apheresis and new therapies for severe familial hypercholesterolemia in adults and children. Best Practice & Research Clinical Endocri- nology & Metabolism. 2013;28:387–403.
49. O’Brien EC, Roe MT, Fraulo ES, et al. Rationale and design of the familial hypercholesterolemia foundation CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia registry. Am Heart J. 2014;167:342–349.e317.
50. Hammond E, Watts GF, Rubinstein Y, et al. Role of international reg- istries in enhancing the care of familial hypercholesterolaemia. Int J Evid Based Healthc. 2013;11:134–139.
51. Health Quality Ontario. Low-density lipoprotein apheresis: an evidence-based analysis. Ont Health Technol Assess Ser. 2007;7: 1–101.
52. Ademi Z, Watts GF, Juniper A, Liew D. A systematic review of eco- nomic evaluations of the detection and treatment of familial hypercho- lesterolemia. Int J Cardiol. 2013;167:2391–2396.
53. Bertolini S, Cassanelli S, Garuti R, et al. Analysis of LDL recep- tor gene mutations in Italian patients with homozygous familial
hypercholesterolemia. Arterioscler Thromb Vasc Biol. 1999;19:
54. Raal F, Panz V, Immelman A, Pilcher G. Elevated PCSK9 Levels in
Untreated Patients With Heterozygous or Homozygous Familial Hypercholesterolemia and the Response to High-Dose Statin Therapy. J Am Heart Assoc. 2013;2:e000028.
55. Umans-Eckenhausen MAW, Defesche JC, Sijbrands EJG, Scheerder RLJM, Kastelein JJP. Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands. Lancet. 2001; 357:165–168.
56. Nherera L, Marks D, Minhas R, Thorogood M, Humphries SE. Prob- abilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies. Heart. 2011;97:1175–1181.
57. Ademi Z, Watts GF, Pang J, et al. Cascade Screening Based on Genetic Testing is Cost-effective: Evidence for the Implementation of Models of Care for Familial Hypercholesterolaemia. J Clin Lipidol. 2014;8:390–400.
58. Humphries SE, Norbury G, Leigh S, Hadfield SG, Nair D. What is the clinical utility of DNA testing in patients with familial hypercholester- olaemia? Curr Opin Lipidol. 2008;19:362–368.
59. Daniels SR, Gidding SS, de Ferranti SD. Pediatric aspects of Familial Hypercholesterolemias: Recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S30–S37.
60. Descamps OS, Tenoutasse S, Stephenne X, et al. Management of familial hypercholesterolemia in children and young adults: Consensus paper developed by a panel of lipidologists, cardiologists, paediatricians, nutritionists, gastroenterologists, general practitioners and a patient organization. Atherosclerosis. 2011;218:272–280.
61. van der Valk FM, van Wijk DF, Stroes ES. Novel anti-inflammatory strategies in atherosclerosis. Curr Opin Lipidol. 2012;23:532–539.
62. Weissleder R, Nahrendorf M, Pittet MJ. Imaging macrophages with nanoparticles. Nat Mater. 2014;13:125–138.
63. Keen HI, Krishnarajah J, Bates TR, Watts GF. Statin myopathy: the fly in the ointment for the prevention of cardiovascular disease in the 21st century? Expert Opin Drug Saf. 2014;13:1227–1239.